The rational design of drugs to be used for chemotherapy is contingent upon (a) choosing a system which, if controlled, will have dramatic effects upon cellular function, and (b) achieving selective toxicity (viz. destruction of the cancer or invading cell under conditions which minimally effect the normal cell). The long-term objective of this proposal is to develop rational methods for control of cellular function which will demonstrate tissue and species selectivity and thus be of use in treatment of disease. Specifically, the systems which will be investigated were chosen because of their central importance in protein biosynthesis and regulation of growth-control: selective modulation of these systems would be of great value to chemotherapy in general and cancer chemotherapy in particular. We shall study a number of mammalian aminoacyl-tRNA synthetases. Our objectives are (1) to develop potent and specific inhibitors of these enzymes, (2) to demonstrate the efficacy and specificity of these enzymes in vivo, (3) to ascertain if these inhibitors induce central regulatory mechanisms of growth contol, and (4) to ascertain whether they have a different effect on normal and neoplastic cells. A hypothesis is forwarded that arrest of normal mammalian cells in Gl interval of the cell cycle is accompanied by, and perhaps triggered by, increases in intracellular uncharged/charged tRNA ratios. Experiments are proposed which will support or negate this hypothesis, and we will attempt to induce this regulatory response with specific inhibitors of the aminoacyl-tRNA synthetases we shall design. Many tranformed cells do not undergo this response; thus, such inhibitors might be useful chemotherapeutic agents by virtue of their cytotoxicity on neoplastic cells, or their protective effects on normal cells.